Abstract 318: Glibenclamide May Have a Neuroprotective and Cardioprotective Role Beyond Cerebral Edema in an Asphyxial Model of Cardiac Arrest

Abstract

Background: Cardiac arrest (CA) is a leading cause of mortality and long-term disability. There are no therapeutics approved for neuro- and cardio-protection. Novel therapeutics are urgently needed to improve patient outcomes. Glibenclamide is a second-generation sulfonylurea drug and inhibitor of SUR1-TRPM4. Little is known about its role in cardioprotection and synaptic density. Aims: To evaluate the effect of glibenclamide on coronary flow reserve (CFR), blood-brain barrier (BBB) permeability, and synaptic density in an asphyxial mouse model of CA. Methods: We used an asphyxial mouse model of CA; potassium chloride was injected into the right internal jugular vein, resulting in asystole. Chest compressions and epinephrine were administered following 12 minutes of no-flow time. Successfully resuscitated mice (n=24) were randomized to receive intravenous glibenclamide or vehicle; the glibenclamide group received a loading dose of 10 μg/kg immediately upon return of spontaneous circulation followed by 1.6 μg every 12 hours up to day 3. Pulse Doppler Velocity (PWV) was used to monitor the CFR and left carotid artery velocity. Synaptic density was quantified with ex vivo autoradiographs after injection of 18 F-SynVesT-2 in the brain (3, 24, and 72 hrs). Evans blue staining and general neurologic deficit scores were assessed 24 hours post-resuscitation. Results: Treatment with glibenclamide resulted in an increase in CFR (1.37±0.11 vs. 1.17±0.06, p=0.01) and carotid peak velocity (61.38±12.81 cm/s vs. 46.83±6.3 cm/s, p<0.05). Whole brain synaptic density was increased in the mice treated with glibenclamide, suggesting a reduction in synaptic density loss. BBB disruption in the cerebrum was significantly lower in Glibenclamide treated mice (0.00022±0.000014/mg vs. 0.000471±0.000088/mg, p<0.01). Mice treated with Glibenclamide had lower neurologic deficit scores (1.83±2.89 vs 4.75±3.84, p<0.05). Conclusions: Glibenclamide given immediately following the return of spontaneous circulation improved CFR, decreased BBB disruption, reduced synaptic density loss, and improved neurologic deficit scores, suggesting both cardio- and neuro-protective effects.